Cell culture and mouse
studies identified androgen receptor antagonists that could help treat
prostate cancers that acquire resistance to Xtandi enzalutamide.
Structural modeling and in vitro mutagenesis assays identified F876L
as a mutation in the androgen receptor that prevents antagonism by Xtandi and
instead causes the drug to behave as a partial agonist. A series of compounds
with D-ring substitutions to the enzalutamide scaffold were synthesized and
shown to inhibit the F876L mutant androgen receptor. In mouse xenograft
models for prostate cancer and in cell lines, the lead D-ring-substituted
compound inhibited growth of F876L mutant prostate cancers, whereas
enzalutamide did not. Next steps include evaluating the lead compound in
additional mouse xenograft models for prostate cancer and determining the
clinical relevance of the mutation.Medivation Inc. and Astellas Pharma Inc. market
Xtandi, a triple-acting oral antiandrogen receptor, to treat
castration-resistant prostate cancer.Aragon Pharmaceuticals Inc.'s
ARN-509, a
second-generation androgen receptor antagonist, is in Phase II testing to
treat prostate cancer.
Corresponding author Charles Sawyers is a cofounder of Aragon Pharmaceuticals
and a co-inventor of both Xtandi and ARN-509 (see Rational approach to
Xtandi resistance, page 1).

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